Asymmetric synthesis of (+)-pyrido[3,4-b]homotropane

(+)-Pyrido[3,4-b]homotropane (PHT) was efficiently constructed in 12 steps from N,N-diisopropylisonicotinamide. The synthesis features (i) RCM reaction in installing the homotropane skeleton, (ii) Snieckus ortho-lithiation of N,N-diisopropylisonicotinamide followed by acylation, (iii) Myer reduction of bulky tertiary amide to alcohol with LiBH3NH2, and (iv) utilization of L-glutamic acid to introduce and establish the requisite stereogenic centers.